Project Summary/Abstract Recent studies have shown that individualized therapies adjusted using specific biomarkers can significantly improve outcomes for patients with chronic diseases, such as chronic kidney disease (CKD), reducing the rate of progression. However, broad application such strategies requires improvement in prognostic markers and tools to enhance monitoring capacity, accuracy, and frequency. With advances in metabolomics revealing new biomarkers with promise for tracking progression and providing actionable data, there is a need to develop tools for self-monitoring that enable patients to take action and more intensively manage their condition. This project aims to address this problem by developing a novel sensor that enables frequent, noninvasive measurement of metabolite biomarkers. The proposed solution utilizes a tiny, injectable, passive ?chemo-optical transducer? and an optical system to noninvasively measure Surface-Enhanced Raman Scattering (SERS) spectra. This concept is based on the PI?s prior success in developing implantable sensors using biocompatible hydrogels, but employs a new approach for broad application to a variety of targets. Feasibility of this sensing platform requires proof of selective, sensitive, and reversible sensing materials, as well as evidence that the target biomarkers are present in the interstitial space around implants. Towards this goal, two independent Specific Aims have been identified to test the overall hypothesis that SERS- enabled implants may be used to track metabolites of relevance to state of chronic disease. Aim 1 will involve evaluation of the protective value provided by encapsulation for three types of nanomaterial-based sensing assays (direct, indirect, affinity). Functionality in the presence of complex medium will be quantified to evaluate performance and effectiveness of encapsulation and hydrogel embedding for protection against interferences. In Aim 2, the conditions of under which subcutaneous implants may be used for metabolic monitoring will be determined, including (a) optical interrogation of implanted SERS-enabled hydrogels to identify material requirements, depth limitations, and effects of host response on measured signals and (b) elucidation of metabolite balance between blood and interstitial compartments. If successful, this project will lay the groundwork for developing a broad spectrum of metabolite sensors, including enabling multianalyte systems to simultaneously monitor several targets. This capability will increase the throughput of animal experiments to study chronic diseases as well as provide a basis for clinical metabolomics studies with enhanced information density and temporal resolution. If successful, this project will support further development of technology to provide chronic disease patients and caregivers more complete information to properly stage and track progression of the disease. Beyond the biomarkers studied, this approach may be adapted to other targets. Ultimately, these tools will allow more frequent assessment of health status, allowing more refined personalized therapy that will improve quality of life.